Target Binding Site Detail
| Target General Information | Top | ||||
|---|---|---|---|---|---|
| Target ID | T60631 | Target Info | |||
| Target Name | Proto-oncogene c-Ret (RET) | ||||
| Synonyms | RET51; RET receptor tyrosine kinase; RET mutant Y791F; RET mutant V804M; RET mutant V804L; RET mutant S891A; RET mutant M918T; RET mutant G691S; Proto-oncogene tyrosine-protein kinase receptor Ret; PTC; Cadherin family member 12; CDHR16; CDHF12; C-ret | ||||
| Target Type | Successful Target | ||||
| Gene Name | RET | ||||
| Biochemical Class | Kinase | ||||
| UniProt ID | |||||
| Ligand General Information | Top | ||||
|---|---|---|---|---|---|
| Ligand Name | Phosphonotyrosine | Ligand Info | |||
| Canonical SMILES | C1=CC(=CC=C1CC(C(=O)O)N)OP(=O)(O)O | ||||
| InChI | 1S/C9H12NO6P/c10-8(9(11)12)5-6-1-3-7(4-2-6)16-17(13,14)15/h1-4,8H,5,10H2,(H,11,12)(H2,13,14,15)/t8-/m0/s1 | ||||
| InChIKey | DCWXELXMIBXGTH-QMMMGPOBSA-N | ||||
| PubChem Compound ID | 30819 | ||||
| Drug Binding Sites of Target | Top | |||||
|---|---|---|---|---|---|---|
| PDB ID: 5FM3 Crystal structure of hyper-phosphorylated RET kinase domain with (proximal) juxtamembrane segment | ||||||
| Method | X-ray diffraction | Resolution | 2.95 Å | Mutation | No | [1] |
| PDB Sequence |
DAFKILEDPK
716 WEFPRKNLVL726 GKTLGEGEFG736 KVVKATAFHL746 KGRAGYTTVA756 VKMLKENASP 766 SELRDLLSEF776 NVLKQVNHPH786 VIKLYGACSQ796 DGPLLLIVEY806 AKGSLRGFLR 817 ESALTMGDLI852 SFAWQISQGM862 QYLAEMKLVH872 RDLAARNILV882 AEGRKMKISD 892 FGLSRDVYEE902 DSVKRQGRIP914 VKWMAIESLF924 DHITTQSDVW935 SFGVLLWEIV 945 TLGGNPYPGI955 PPERLFNLLK965 TGHRMERPDN975 CSEEMYRLML985 QCWKQEPDKR 995 PVFADISKDL1005 EKMMVK
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ALA807
3.267
LYS808
1.327
GLY810
1.329
SER811
3.730
PHE815
3.763
GLU818
4.784
VAL871
4.002
ARG873
3.095
VAL882
3.203
ALA883
3.134
GLU884
3.660
GLY885
2.584
ARG886
3.468
ARG897
3.697
ASP903
3.437
|
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| PDB ID: 5FM2 Crystal structure of hyper-phosphorylated RET kinase domain with (proximal) juxtamembrane segment | ||||||
| Method | X-ray diffraction | Resolution | 3.30 Å | Mutation | No | [1] |
| PDB Sequence |
KILEDPKWEF
719 PRKNLVLGKT729 LGEGEFGKVV739 KATAFHLKGR749 AGYTTVAVKM759 LKENASPSEL 769 RDLLSEFNVL779 KQVNHPHVIK789 LYGACSQDGP799 LLLIVEYAKG810 SLRGFLRESA 845 LTMGDLISFA855 WQISQGMQYL865 AEMKLVHRDL875 AARNILVAEG885 RKMKISDFGL 895 SRDVYEEDSV906 KRQGRIPVKW917 MAIESLFDHI927 TTQSDVWSFG938 VLLWEIVTLG 948 GNPYPGIPPE958 RLFNLLKTGH968 RMERPDNCSE978 EMYRLMLQCW988 KQEPDKRPVF 998 ADISKDLEKM1008 MVK
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ALA807
3.427
LYS808
1.329
GLY810
1.330
SER811
4.111
PHE815
3.821
GLU818
4.640
VAL871
4.288
ARG873
3.412
VAL882
3.014
ALA883
3.111
GLU884
3.621
GLY885
2.687
ARG886
3.785
ARG897
3.406
ASP903
3.477
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| PDB ID: 7RUN Crystal structure of phosphorylated RET tyrosine kinase domain complexed with a pyrrolo[2,3-d]pyrimidine inhibitor. | ||||||
| Method | X-ray diffraction | Resolution | 3.51 Å | Mutation | No | [2] |
| PDB Sequence |
SVDAFKILED
714 PKWEFPRKNL724 VLGKTLGEGE734 FGKVVKATAF744 HLKGRAGYTT754 VAVKMLKENA 764 SPSELRDLLS774 EFNVLKQVNH784 PHVIKLYGAC794 SQDGPLLLIV804 EYAKGSLRGF 815 LRESRKVRAL846 TMGDLISFAW856 QISQGMQYLA866 EMKLVHRDLA876 ARNILVAEGR 886 KMKISDFGLS896 RDVYEEDSVK907 RQGRIPVKWM918 AIESLFDHIT929 TQSDVWSFGV 939 LLWEIVTLGG949 NPYPGIPPER959 LFNLLKTGHR969 MERPDNCSEE979 MYRLMLQCWK 989 QEPDKRPVFA999 DISKDLEKMM1009 VKR
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ALA807
3.267
LYS808
1.330
GLY810
1.329
SER811
4.246
PHE815
3.918
GLU818
4.546
VAL871
3.475
ARG873
3.560
VAL882
3.291
ALA883
3.111
GLU884
2.387
GLY885
1.297
ARG886
3.028
ARG897
3.836
ASP903
3.178
|
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| PDB ID: 4CKJ Crystal structure of RET tyrosine kinase domain bound to adenosine | ||||||
| Method | X-ray diffraction | Resolution | 1.65 Å | Mutation | No | [3] |
| PDB Sequence |
GPLSLSVDAF
709 KILEDPKWEF719 PRKNLVLGKT729 LGEGEFGKVV739 KATAFHLKGR749 AGYTTVAVKM 759 LKENASPSEL769 RDLLSEFNVL779 KQVNHPHVIK789 LYGACSQDGP799 LLLIVEYAKY 809 GSLRGFLRES819 RKVRALTMGD850 LISFAWQISQ860 GMQYLAEMKL870 VHRDLAARNI 880 LVAEGRKMKI890 SDFGLSRDVY900 EEDSVKRSQG911 RIPVKWMAIE921 SLFDHIYTTQ 931 SDVWSFGVLL941 WEIVTLGGNP951 YPGIPPERLF961 NLLKTGHRME971 RPDNCSEEMY 981 RLMLQCWKQE991 PDKRPVFADI1001 SKDLEKMMVK1011 RR
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Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .PTR or .PTR2 or .PTR3 or :3PTR;style chemicals stick;color identity;select .A:770 or .A:873 or .A:897 or .A:899 or .A:903 or .A:904 or .A:906 or .A:907 or .A:926 or .A:927 or .A:928; color #f3c393; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
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| PDB ID: 6I83 Crystal structure of phosphorylated RET V804M tyrosine kinase domain complexed with PDD00018366 | ||||||
| Method | X-ray diffraction | Resolution | 1.88 Å | Mutation | Yes | [4] |
| PDB Sequence |
GPLSLSVDAF
709 KILEDPKWEF719 PRKNLVLGKT729 LGEGEFGKVV739 KATAFHLKGR749 AGYTTVAVKM 759 LKENASPSEL769 RDLLSEFNVL779 KQVNHPHVIK789 LYGACSQDGP799 LLLIMEYAKY 809 GSLRGFLRES819 RKRALTMGDL851 ISFAWQISQG861 MQYLAEMKLV871 HRDLAARNIL 881 VAEGRKMKIS891 DFGLSRDVYE901 EDSVKRSQGR912 IPVKWMAIES922 LFDHIYTTQS 932 DVWSFGVLLW942 EIVTLGGNPY952 PGIPPERLFN962 LLKTGHRMER972 PDNCSEEMYR 982 LMLQCWKQEP992 DKRPVFADIS1002 KDLEKMMVKR1012 R
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Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .PTR or .PTR2 or .PTR3 or :3PTR;style chemicals stick;color identity;select .A:770 or .A:873 or .A:897 or .A:899 or .A:903 or .A:904 or .A:906 or .A:907 or .A:926 or .A:927 or .A:928 or .A:929; color #00ffc7; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
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| PDB ID: 6NJA Structure of WT RET protein tyrosine kinase domain at 1.92A resolution. | ||||||
| Method | X-ray diffraction | Resolution | 1.92 Å | Mutation | No | [5] |
| PDB Sequence |
GPLSLSVDAF
709 KILEDPKWEF719 PRKNLVLGKT729 LGEGEFGKVV739 KATAFHLKGR749 AGYTTVAVKM 759 LKENASPSEL769 RDLLSEFNVL779 KQVNHPHVIK789 LYGACSQDGP799 LLLIVEYAKY 809 GSLRGFLRES819 RKVERALTMG849 DLISFAWQIS859 QGMQYLAEMK869 LVHRDLAARN 879 ILVAEGRKMK889 ISDFGLSRDV899 EEDSVKRSQG911 RIPVKWMAIE921 SLFDHIYTTQ 931 SDVWSFGVLL941 WEIVTLGGNP951 YPGIPPERLF961 NLLKTGHRME971 RPDNCSEEMY 981 RLMLQCWKQE991 PDKRPVFADI1001 SKDLEKMMVK1011 RR
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Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .PTR or .PTR2 or .PTR3 or :3PTR;style chemicals stick;color identity;select .A:770 or .A:869 or .A:873 or .A:897 or .A:898 or .A:899 or .A:901 or .A:902 or .A:903 or .A:904 or .A:906 or .A:907 or .A:926 or .A:927 or .A:928 or .A:929; color #f3c393; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
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| PDB ID: 6NE7 Structure of G810A mutant of RET protein tyrosine kinase domain. | ||||||
| Method | X-ray diffraction | Resolution | 1.99 Å | Mutation | Yes | [5] |
| PDB Sequence |
GPLSLSVDAF
709 KILEDPKWEF719 PRKNLVLGKT729 LGEGEFGKVV739 KATAFHLKGR749 AGYTTVAVKM 759 LKENASPSEL769 RDLLSEFNVL779 KQVNHPHVIK789 LYGACSQDGP799 LLLIVEYAKY 809 ASLRGFLRES819 RKVGERALTM848 GDLISFAWQI858 SQGMQYLAEM868 KLVHRDLAAR 878 NILVAEGRKM888 KISDFGLSRD898 VEEDSVKRSQ910 GRIPVKWMAI920 ESLFDHIYTT 930 QSDVWSFGVL940 LWEIVTLGGN950 PYPGIPPERL960 FNLLKTGHRM970 ERPDNCSEEM 980 YRLMLQCWKQ990 EPDKRPVFAD1000 ISKDLEKMMV1010 KRR
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Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .PTR or .PTR2 or .PTR3 or :3PTR;style chemicals stick;color identity;select .A:770 or .A:869 or .A:871 or .A:873 or .A:897 or .A:898 or .A:899 or .A:901 or .A:902 or .A:903 or .A:904 or .A:906 or .A:907 or .A:926 or .A:927 or .A:928 or .A:929; color #00ffc7; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
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| PDB ID: 2X2L Crystal Structure of phosphorylated RET tyrosine kinase domain with inhibitor | ||||||
| Method | X-ray diffraction | Resolution | 2.00 Å | Mutation | No | [6] |
| PDB Sequence |
GPLSLSVDAF
709 KILPKWEFPR721 KNLVLGKTLG731 EGEFGKVVKA741 TAFHLKGRAG751 YTTVAVKMLK 761 ENASPSELRD771 LLSEFNVLKQ781 VNHPHVIKLY791 GACSQDGPLL801 LIVEYAKYGS 811 LRGFLRESRK821 VRALTMGDLI852 SFAWQISQGM862 QYLAEMKLVH872 RDLAARNILV 882 AEGRKMKISD892 FGLSRDVYEE902 DSVKRSQGRI913 PVKWMAIESL923 FDHIYTTQSD 933 VWSFGVLLWE943 IVTLGGNPYP953 GIPPERLFNL963 LKTGHRMERP973 DNCSEEMYRL 983 MLQCWKQEPD993 KRPVFADISK1003 DLEKMMV
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Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .PTR or .PTR2 or .PTR3 or :3PTR;style chemicals stick;color identity;select .A:770 or .A:873 or .A:897 or .A:899 or .A:903 or .A:904 or .A:906 or .A:907 or .A:926 or .A:927 or .A:928 or .A:929; color #f3c393; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
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| PDB ID: 6I82 Crystal structure of partially phosphorylated RET V804M tyrosine kinase domain complexed with PDD00018412 | ||||||
| Method | X-ray diffraction | Resolution | 2.05 Å | Mutation | Yes | [4] |
| PDB Sequence |
GPLSLSVDAF
709 KILEDPKWEF719 PRKNLVLGKT729 LGEGEFGKVV739 KATAFHLKGR749 AGYTTVAVKM 759 LKENASPSEL769 RDLLSEFNVL779 KQVNHPHVIK789 LYGACSQDGP799 LLLIMEYAKY 809 GSLRGFLRES819 ERALTMGDLI852 SFAWQISQGM862 QYLAEMKLVH872 RDLAARNILV 882 AEGRKMKISD892 FGLSRDVYQG911 RIPVKWMAIE921 SLFDHITTQS932 DVWSFGVLLW 942 EIVTLGGNPY952 PGIPPERLFN962 LLKTGHRMER972 PDNCSEEMYR982 LMLQCWKQEP 992 DKRPVFADIS1002 KDLEKMMVKR1012
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Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .PTR or .PTR2 or .PTR3 or :3PTR;style chemicals stick;color identity;select .A:871 or .A:873 or .A:899 or .A:910 or .A:911 or .A:912 or .A:913 or .A:918 or .A:922 or .A:923 or .A:926 or .A:927 or .A:929 or .A:930 or .A:932; color #00ffc7; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
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| PDB ID: 4CKI Crystal Structure of oncogenic RET tyrosine kinase M918T bound to adenosine | ||||||
| Method | X-ray diffraction | Resolution | 2.12 Å | Mutation | Yes | [3] |
| PDB Sequence |
GPLSLSVDAF
709 KILEDPKWEF719 PRKNLVLGKT729 LGEGEFGKVV739 KATAFHLKGR749 AGYTTVAVKM 759 LKENASPSEL769 RDLLSEFNVL779 KQVNHPHVIK789 LYGACSQDGP799 LLLIVEYAKY 809 GSLRGFLRES819 RKVDERALTM848 GDLISFAWQI858 SQGMQYLAEM868 KLVHRDLAAR 878 NILVAEGRKM888 KISDFGLSRD898 VEEDSVKRSQ910 GRIPVKWTAI920 ESLFDHIYTT 930 QSDVWSFGVL940 LWEIVTLGGN950 PYPGIPPERL960 FNLLKTGHRM970 ERPDNCSEEM 980 YRLMLQCWKQ990 EPDKRPVFAD1000 ISKDLEKMMV1010 KRR
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Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .PTR or .PTR2 or .PTR3 or :3PTR;style chemicals stick;color identity;select .A:770 or .A:869 or .A:873 or .A:897 or .A:898 or .A:899 or .A:901 or .A:902 or .A:903 or .A:904 or .A:906 or .A:907 or .A:926 or .A:927 or .A:928; color #f3c393; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
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| PDB ID: 2IVV Crystal structure of phosphorylated RET tyrosine kinase domain complexed with the inhibitor PP1 | ||||||
| Method | X-ray diffraction | Resolution | 2.25 Å | Mutation | No | [7] |
| PDB Sequence |
GPLSLSVDAF
709 KIKWEFPRKN723 LVLGKTLGEG733 EFGKVVKATA743 FHLKGRAGYT753 TVAVKMLKEN 763 ASPSELRDLL773 SEFNVLKQVN783 HPHVIKLYGA793 CSQDGPLLLI803 VEYAKYGSLR 813 GFLRESRLTM848 GDLISFAWQI858 SQGMQYLAEM868 SLVHRDLAAR878 NILVAEGRKM 888 KISDFGLSRD898 VYEEDSVKRS909 QGRIPVKWMA919 IESLFDHIYT929 TQSDVWSFGV 939 LLWEIVTLGG949 NPYPGIPPER959 LFNLLKTGHR969 MERPDNCSEE979 MYRLMLQCWK 989 QEPDKRPVFA999 DISKDLEKMM1009 VK
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Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .PTR or .PTR2 or .PTR3 or :3PTR;style chemicals stick;color identity;select .A:770 or .A:871 or .A:873 or .A:897 or .A:899 or .A:903 or .A:904 or .A:906 or .A:907 or .A:926 or .A:927 or .A:928; color #00ffc7; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
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| PDB ID: 7NZN Structure of RET kinase domain bound to inhibitor JB-48 | ||||||
| Method | X-ray diffraction | Resolution | 2.39 Å | Mutation | No | [8] |
| PDB Sequence |
GPLSLSVDAF
709 KIDPKWEFPR721 KNLVLGKTLG731 EGEFGKVVKA741 TAFHLKGRAG751 YTTVAVKMLK 761 ENASPSELRD771 LLSEFNVLKQ781 VNHPHVIKLY791 GACSQDGPLL801 LIVEYAKYGS 811 LRGFLRESRR844 ALTMGDLISF854 AWQISQGMQY864 LAEMKLVHRD874 LAARNILVAE 884 GRKMKISDFG894 LSRDVEEDSV906 KRSQGRIPVK916 WMAIESLFDH926 IYTTQSDVWS 936 FGVLLWEIVT946 LGGNPYPGIP956 PERLFNLLKT966 GHRMERPDNC976 SEEMYRLMLQ 986 CWKQEPDKRP996 VFADISKDLE1006 KMMVKRR
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Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .PTR or .PTR2 or .PTR3 or :3PTR;style chemicals stick;color identity;select .A:770 or .A:868 or .A:869 or .A:871 or .A:873 or .A:897 or .A:898 or .A:899 or .A:901 or .A:902 or .A:903 or .A:904 or .A:906 or .A:907 or .A:926 or .A:927 or .A:928 or .A:929; color #f3c393; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
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| PDB ID: 2IVU Crystal structure of phosphorylated RET tyrosine kinase domain complexed with the inhibitor ZD6474 | ||||||
| Method | X-ray diffraction | Resolution | 2.50 Å | Mutation | No | [7] |
| PDB Sequence |
GPLSLSVDAF
709 KILDPKWEFP720 RKNLVLGKTL730 GEGEFGKVVK740 ATAFHLKGRA750 GYTTVAVKML 760 KENASPSELR770 DLLSEFNVLK780 QVNHPHVIKL790 YGACSQDGPL800 LLIVEYAKYG 810 SLRGFLRESR820 RALTMGDLIS853 FAWQISQGMQ863 YLAEMKLVHR873 DLAARNILVA 883 EGRKMKISDF893 GLSRDVYEED903 SVKRSQGRIP914 VKWMAIESLF924 DHIYTTQSDV 934 WSFGVLLWEI944 VTLGGNPYPG954 IPPERLFNLL964 KTGHRMERPD974 NCSEEMYRLM 984 LQCWKQEPDK994 RPVFADISKD1004 LEKMMVKR
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Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .PTR or .PTR2 or .PTR3 or :3PTR;style chemicals stick;color identity;select .A:770 or .A:871 or .A:873 or .A:897 or .A:899 or .A:903 or .A:904 or .A:906 or .A:907 or .A:926 or .A:927 or .A:928; color #00ffc7; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
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| PDB ID: 2X2M Crystal Structure of phosphorylated RET tyrosine kinase domain with inhibitor | ||||||
| Method | X-ray diffraction | Resolution | 2.50 Å | Mutation | No | [6] |
| PDB Sequence |
GPLSLSVDAF
709 KILDPKWEFP720 RKNLVLGKTL730 GEFGKVVKAT742 AFHLKGRAGY752 TTVAVKMLKE 762 NASPSELRDL772 LSEFNVLKQV782 NHPHVIKLYG792 ACSQDGPLLL802 IVEYAKYGSL 812 RGFLRESRAL846 TMGDLISFAW856 QISQGMQYLA866 EMKLVHRDLA876 ARNILVAEGR 886 KMKISDFGLS896 RDVYEEDSVK907 RSQGRIPVKW917 MAIESLFDHI927 YTTQSDVWSF 937 GVLLWEIVTL947 GGNPYPGIPP957 ERLFNLLKTG967 HRMERPDNCS977 EEMYRLMLQC 987 WKQEPDKRPV997 FADISKDLEK1007 MMVKRR
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Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .PTR or .PTR2 or .PTR3 or :3PTR;style chemicals stick;color identity;select .A:770 or .A:871 or .A:873 or .A:897 or .A:899 or .A:903 or .A:904 or .A:906 or .A:907 or .A:926 or .A:927 or .A:928; color #f3c393; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
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| PDB ID: 2IVT Crystal structure of phosphorylated RET tyrosine kinase domain | ||||||
| Method | X-ray diffraction | Resolution | 2.60 Å | Mutation | No | [7] |
| PDB Sequence |
GPLSLSVDAF
709 KIPKWEFPRK722 NLVLGKTLGE732 GEFGKVVKAT742 AFHLKGRAGY752 TTVAVKMLKE 762 NASPSELRDL772 LSEFNVLKQV782 NHPHVIKLYG792 ACSQDGPLLL802 IVEYAKYGSL 812 RGFLRESRKV822 RALTMGDLIS853 FAWQISQGMQ863 YLAEMKLVHR873 DLAARNILVA 883 EGRKMKISDF893 GLSRDVYEED903 SVKRSQGRIP914 VKWMAIESLF924 DHIYTTQSDV 934 WSFGVLLWEI944 VTLGGNPYPG954 IPPERLFNLL964 KTGHRMERPD974 NCSEEMYRLM 984 LQCWKQEPDK994 RPVFADISKD1004 LEKMMVKR
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Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .PTR or .PTR2 or .PTR3 or :3PTR;style chemicals stick;color identity;select .A:770 or .A:873 or .A:897 or .A:899 or .A:903 or .A:904 or .A:906 or .A:907 or .A:926 or .A:927 or .A:928 or .A:929; color #00ffc7; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
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||||||
| PDB ID: 2X2K Crystal Structure of phosphorylated RET tyrosine kinase domain with inhibitor | ||||||
| Method | X-ray diffraction | Resolution | 2.60 Å | Mutation | No | [6] |
| PDB Sequence |
GPLSLSVDAF
709 KIPKWEFPRK722 NLVLGKTLGE732 GEFGKVVKAT742 AFHLKGRAGY752 TTVAVKMLKE 762 NASPSELRDL772 LSEFNVLKQV782 NHPHVIKLYG792 ACSQDGPLLL802 IVEYAKYGSL 812 RGFLRESRKV822 RALTMGDLIS853 FAWQISQGMQ863 YLAEMKLVHR873 DLAARNILVA 883 EGRKMKISDF893 GLSRDVYEED903 SVKRSQGRIP914 VKWMAIESLF924 DHIYTTQSDV 934 WSFGVLLWEI944 VTLGGNPYPG954 IPPERLFNLL964 KTGHRMERPD974 NCSEEMYRLM 984 LQCWKQEPDK994 RPVFADISKD1004 LEKMMVKRR
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Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .PTR or .PTR2 or .PTR3 or :3PTR;style chemicals stick;color identity;select .A:770 or .A:873 or .A:897 or .A:899 or .A:903 or .A:904 or .A:906 or .A:907 or .A:926 or .A:927 or .A:928 or .A:929; color #f3c393; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
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| PDB ID: 6VHG Crystal structure of phosphorylated RET tyrosine kinase domain complexed with a pyrazolo[1,5-a]pyrimidine inhibitor | ||||||
| Method | X-ray diffraction | Resolution | 2.30 Å | Mutation | No | [9] |
| PDB Sequence |
DAFKILEDPK
716 WEFPRKNLVL726 GKTLGEGEFG736 KVVKATAFHL746 KGRAGYTTVA756 VKMLKENASP 766 SELRDLLSEF776 NVLKQVNHPH786 VIKLYGACSQ796 DGPLLLIVEY806 AKYGSLRGFL 816 RESRRALTMG849 DLISFAWQIS859 QGMQYLAEMK869 LVHRDLAARN879 ILVAEGRKMK 889 ISDFGLSRDV899 YEEDSVKRSQ910 GRIPVKWMAI920 ESLFDHITTQ931 SDVWSFGVLL 941 WEIVTLGGNP951 YPGIPPERLF961 NLLKTGHRME971 RPDNCSEEMY981 RLMLQCWKQE 991 PDKRPVFADI1001 SKDLEKMMVK1011 R
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Click to Show 3D Structure of This Binding Site
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| PDB ID: 6FEK Oncogenic point mutation of RET receptor tyrosine kinase | ||||||
| Method | X-ray diffraction | Resolution | 2.30 Å | Mutation | Yes | [10] |
| PDB Sequence |
GPLSLSVDAF
709 KILAAPKWEF719 PRKNLVLGKT729 LGEGEFGKVV739 KATAFHLKGR749 AGYTTVAVKM 759 LKENASPSEL769 RDLLSEFNVL779 KQVNHPHVIK789 LYGACSQDGP799 LLLIVEYAKY 809 GSLRGFLRES819 RKVGPGPDER844 ALTMGDLISF854 AWQISQGMQY864 LAEMKLVHRD 874 LAARNILVAE884 GRKMKISDFG894 LSRDVEEDFV906 KRSQGRIPVK916 WMAIESLFDH 926 IYTTQSDVWS936 FGVLLWEIVT946 LGGNPYPGIP956 PERLFNLLKT966 GHRMERPDNC 976 SEEMYRLMLQ986 CWKQEPDKRP996 VFADISKDLE1006 KMMV
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| PDB ID: 5AMN The Discovery of 2-Substituted Phenol Quinazolines as Potent and Selective RET Kinase Inhibitors | ||||||
| Method | X-ray diffraction | Resolution | 2.57 Å | Mutation | No | [11] |
| PDB Sequence |
GPLSLSVDAF
709 KIDPKWEFPR721 KNLVLGKTLG731 EGEFGKVVKA741 TAFHLKGRAG751 YTTVAVKMLK 761 ENASPSELRD771 LLSEFNVLKQ781 VNHPHVIKLY791 GACSQDGPLL801 LIVEYAKYGS 811 LRGFLRESRK821 VERALTMGDL851 ISFAWQISQG861 MQYLAEMKLV871 HRDLAARNIL 881 VAEGRKMKIS891 DFGLSRDVEE902 DSVKRSQGRI913 PVKWMAIESL923 FDHIYTTQSD 933 VWSFGVLLWE943 IVTLGGNPYP953 GIPPERLFNL963 LKTGHRMERP973 DNCSEEMYRL 983 MLQCWKQEPD993 KRPVFADISK1003 DLEKMMV
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| References | Top | ||||
|---|---|---|---|---|---|
| REF 1 | RET Functions as a Dual-Specificity Kinase that Requires Allosteric Inputs from Juxtamembrane Elements. Cell Rep. 2016 Dec 20;17(12):3319-3332. | ||||
| REF 2 | Antitarget Selectivity and Tolerability of Novel Pyrrolo[2,3-d]pyrimidine RET Inhibitors. ACS Med Chem Lett. 2021 Nov 6;12(12):1912-1919. | ||||
| REF 3 | Oncogenic RET kinase domain mutations perturb the autophosphorylation trajectory by enhancing substrate presentation in trans. Mol Cell. 2014 Mar 6;53(5):738-51. | ||||
| REF 4 | Discovery and Optimization of wt-RET/KDR-Selective Inhibitors of RET(V804M) Kinase. ACS Med Chem Lett. 2020 Feb 28;11(4):497-505. | ||||
| REF 5 | Structural basis of resistance of mutant RET protein-tyrosine kinase to its inhibitors nintedanib and vandetanib. J Biol Chem. 2019 Jul 5;294(27):10428-10437. | ||||
| REF 6 | Synthesis, structure-activity relationship and crystallographic studies of 3-substituted indolin-2-one RET inhibitors. Bioorg Med Chem. 2010 Feb 15;18(4):1482-96. | ||||
| REF 7 | Structure and chemical inhibition of the RET tyrosine kinase domain. J Biol Chem. 2006 Nov 3;281(44):33577-87. | ||||
| REF 8 | Discovery of N-Trisubstituted Pyrimidine Derivatives as Type I RET and RET Gatekeeper Mutant Inhibitors with a Novel Kinase Binding Pose. J Med Chem. 2022 Jan 27;65(2):1536-1551. | ||||
| REF 9 | Efficacy and Tolerability of Pyrazolo[1,5-a]pyrimidine RET Kinase Inhibitors for the Treatment of Lung Adenocarcinoma. ACS Med Chem Lett. 2020 Feb 12;11(4):558-565. | ||||
| REF 10 | A secondary RET mutation in the activation loop conferring resistance to vandetanib. Nat Commun. 2018 Feb 12;9(1):625. | ||||
| REF 11 | The discovery of 2-substituted phenol quinazolines as potent RET kinase inhibitors with improved KDR selectivity. Eur J Med Chem. 2016 Apr 13;112:20-32. | ||||
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